Processes for the preparation of pesticidal compounds

ABSTRACT

The present application provides processes for making pesticidal compounds and compounds useful both as pesticides and in the making of pesticidal compounds.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No. 14/829,174filed on Aug. 18, 2015, which is a divisional of U.S. application Ser.No. 14/517,594 filed on Oct. 17, 2014, which claims the benefit of U.S.Provisional Patent Applications: Ser. No. 62/039,730, filed Aug. 20,2014; and Ser. No. 61/892,118, filed Oct. 17, 2013, the entiredisclosure of these applications are hereby expressly incorporated byreference in to this application.

TECHNICAL FIELD

This application relates to efficient and economical synthetic chemicalprocesses for the preparation of pesticidal thioethers and pesticidalsulfoxides. Further, the present application relates to certain novelcompounds necessary for their synthesis. It would be advantageous toproduce pesticidal thioethers and pesticidal sulfoxides efficiently andin high yield from commercially available starting materials.

DETAILED DESCRIPTION

The following definitions apply to the terms as used throughout thisspecification, unless otherwise limited in specific instances.

As used herein, the term “alkyl” denotes branched or unbranchedhydrocarbon chains.

Unless otherwise indicated, the term “cycloalkyl” as employed hereinalone is a saturated cyclic hydrocarbon group, such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl.

The term “thio” as used herein as part of another group refers to asulfur atom serving as a linker between two groups.

The term “halogen” or “halo” as used herein alone or as part of anothergroup refers to chlorine, bromine, fluorine, and iodine.

The compounds and process of the present application are described indetail below in scheme 1.

In step a of Scheme 1, 4-nitropyrazole is halogenated and reduced toyield 3-chloro-1H-pyrazol-4-amine hydrochloride (1a). The halogenationoccurs at the 3-carbon through the use of concentrated (37 weightpercent) hydrochloric acid (HCl). The reduction occurs withtriethylsilane (Et₃SiH) and palladium on alumina (Pd/Al₂O₃, preferablyabout 1 to 10 weight percent palladium on alumina, more preferably about5 weight percent). This reaction may be conducted at a temperature fromabout 0° C. to about 40° C., preferably from about 10° C. to about 20°C. This reaction may be conducted in a polar protic solvent, such asmethanol (MeOH) or ethanol (EtOH), preferably ethanol. It wassurprisingly discovered, that by utilizing about 1 equivalent to about 4equivalents, preferably, about 2.5 equivalents to about 3.5 equivalentsof triethylsilane in this step, while conducting the reaction betweenabout 10° C. and about 20° C., gives about a 10:1 molar ratio of thedesired halogenated product 3-chloro-1H-pyrazol-4-amine hydrochloride(1a)

versus the undesired product

In step b of Scheme 1, 3-chloro-1H-pyrazol-4-amine hydrochloride (1a) isacylated with acetic anhydride (Ac₂O) in the presence a base, preferablyan inorganic base, such as, sodium bicarbonate (NaHCO₃), at about 0° C.to about 10° C., preferably about 5° C. to yieldN-(3-chloro-1H-pyrazol-4-yl)acetamide (1b). It was surprisinglydiscovered that a chloro substituent must be present at the 3-positionfor this reaction to proceed to completion and to also avoid overacylation. Described herein is a comparative example without a halogenat the 3-position that yielded the double acylated product (see “CE-1”).Further, comparative example with a bromo group at the 3-positionafforded the product in a surprisingly low yield compared to the yieldwith the chloro group (see “CE-2”).

In step c of Scheme 1, N-(3-chloro-1H-pyrazol-4-yl)acetamide (1b) isreacted with a halopyridine such as 3-bromopyridine or 3-iodopyridine inthe presence of a copper salt (such as copper(I) chloride (CuCl),copper(II) chloride (CuCl₂), or copper(I) iodide (CuI)), potassiumphosphate (K₃PO₄), and N,N′-dimethylethane-1,2-diamine to yieldN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)acetamide (1c). It has beendiscovered that when copper(I) iodide is used that the yield of thereaction is greatly affected by the quality of the copper(I) iodide. Theprocess may be conducted in a polar solvent, such as, acetonitrile(MeCN), dioxane, or N,N-dimethylformamide at a temperature between about50° C. and about 110° C. It was surprisingly discovered that theaddition of water during the work-up of this step maximizes the yield.Further, this synthetic method is simpler and reduces the costs ofstarting materials over known heteroarylation methods.

In step d of Scheme 1,N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)acetamide (1c) is reducedin the presence of a hydride source, preferably, sodium borohydride(NaBH₄) and an acid source, such as a Brønsted acid or a Lewis acid,preferably a Lewis acid, preferably borontrifluoride etherate (BF₃Et₂O)to yield 3-chloro-N-ethyl-1-(pyridin-3-yl)-1H-pyrazol-amine (1d). It hasbeen surprisingly discovered that the yield of the reaction is greatlyaffected by the quality of the borontrifluoride etherate (purchased fromdifferent suppliers, currently, Sigma Aldrich product number 175501being preferred).

In step e of Scheme 1,3-chloro-N-ethyl-1-(pyridin-3-yl)-1H-pyrazol-amine (1d) is reacted withbetween about 1 and about 2 equivalents of 3-chloropropionyl chloride inthe presence of an inorganic base, preferably, metal carbonates, metalhydroxides, metal phosphates, metal hydrides, more preferably sodiumbicarbonate to yield3-chloro-N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylpropanamide(2a).

In step f of Scheme 1,3-chloro-N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylpropanamide(2a) is reacted with a thiol (HS-R¹), in the presence of an inorganicbase, preferably, metal carbonates, metal hydroxides, metal phosphates,metal hydrides, more preferably, potassium hydroxide (KOH), conducted inthe presence of a polar solvent, preferably methanol, wherein R¹ isselected from the group consisting of C₁-C₄-haloalkyl andC₁-C₄-alkyl-C₃-C₆-halocycloalkyl, preferably, R¹ is selected fromCH₂CH₂CF₃ or CH₂(2,2-difluorocyclopropyl) to yield thioether (2b).

In step g of Scheme 1, thioether (2b) is oxidized with an oxidant,preferably hydrogen peroxide (H₂O₂) in a polar protic solvent to yieldthe desired pesticidal sulfoxides (2c). Preferred solvents are primaryC₁-C₄-alcohols, especially methanol.

Alternatively, N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)acetamide(1c) may be prepared by the heteroarylation ofN-(3-chloro-1H-pyrazol-4-yl)acetamide (1b) disclosed in Scheme 2,providing further cost savings of this process.

Additionally, 3-chloro-1H-pyrazol-4-amine hydrochloride (1a) may beprepared from 4-nitropyrazole. The 4-nitropyrazole is halogenated at the3-carbon through the use of concentrated hydrochloric acid at about 0°C. to about 40° C., preferably 10° C. to about 20° C. during thereduction with palladium on alumina and hydrogen (H₂) to provide thedescribed product as illustrated in Scheme 3.

3-Chloro-N-ethyl-1-(pyridin-3-yl)-1H-pyrazol-amine (1d) may be preparedthrough the reaction pathway sequence disclosed in Scheme 4. In step d1,N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)acetamide (1c) may bealkylated with ethyl bromide (EtBr) in the presence of a base, such assodium hydride (NaH), sodium tert-butoxide (NaOt-Bu), potassiumtert-butoxide (KOt-Bu), or potassium tert-amyloxide, in a polar aproticsolvent, such as tetrahydrofuran (THF), at temperatures from about 20°C. to about 40° C., over a period of time of about 60 hours to about 168hours, to yieldN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylacetamide (1c′). Ithas been discovered that use of an additive, such as potassium iodide(KI) or tetrabutylammonium iodide (TBAI) decreases the time necessaryfor the reaction to complete to about 24 hours. It was also discoveredthat heating the reaction at about 50° C. to about 70° C. in a sealedreactor (to prevent loss of ethyl bromide) decreases the reaction timeto about 24 hours. In step d2,N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylacetamide (1c′) maybe treated with hydrochloric acid in water at temperatures from about70° C. to about 90° C., to yield3-chloro-N-ethyl-1-(pyridin-3-yl)-1H-pyrazol-amine (1d). The reactionpathway sequence disclosed in Scheme 4 may also be performed without theisolation ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylacetamide (1c′).

EXAMPLES

The following examples are presented to better illustrate the processesof the present application.

COMPOUND EXAMPLES Example 1: 3-Chloro-1H-pyrazol-4-amine hydrochloride(1a)

A 1000-mL, multi-neck cylindrical jacketed reactor, fitted with amechanical stirrer, temperature probe and nitrogen (N₂) inlet, wascharged with 4-nitropyrazole (50.0 g, 429 mmol) and palladium on alumina(5 wt %, 2.5 g). Ethanol (150 mL) was added, followed by a slow additionof concentrated hydrochloric acid (37 wt %, 180 mL). The reaction wascooled to 15° C., and triethylsilane (171 mL, 1072 mmol) was addedslowly via addition funnel over 1 hour, while maintaining the internaltemperature at 15° C. The reaction was stirred at 15° C. for 72 hours,after which the reaction mixture was filtered through a Celite® pad andthe pad was rinsed with warm ethanol (40° C., 2×100 mL). The combinedfiltrates were separated and the aqueous layer (bottom layer) wasconcentrated to ˜100 mL. Acetonitrile (200 mL) was added and theresulting suspension was concentrated to ˜100 mL. Acetonitrile (200 mL)was added and the resulting suspension was concentrated to ˜100 mL.Acetonitrile (200 mL) was added and the resulting suspension was stirredat 20° C. for 1 hour and filtered. The filter cake was rinsed withacetonitrile (2×100 mL) and dried under vacuum at 20° C. to afford awhite solid (˜10:1 mixture of 1a and 1H-pyrazol-4-amine, 65.5 g, 99%):¹H NMR (400 MHz, DMSO-d₆) δ 10.52 (bs, 3H), 8.03 (s, 1H); EIMS m/z 117([M]⁺).

Example 2: N-(3-Chloro-1H-pyrazol-4-yl)acetamide (1b)

A 100-mL 3-neck round bottom flask was charged with3-chloro-1H-pyrazol-4-amine-hydrochloride (5.00 g, 32.5 mmol) and water(25 mL). Sodium bicarbonate (10.9 g, 130 mmol) was added slowly over 10minutes (off-gassing during addition), followed by tetrahydrofuran (25mL). The mixture was cooled to 5° C. and acetic anhydride (3.48 g, 34.1mmol) was added over 30 minutes while maintaining the internaltemperature at <10° C. The reaction was stirred at 5° C. for 1 hour, atwhich point thin layer chromatography (TLC) analysis [Eluent: ethylacetate (EtOAc)] indicated that the starting material had disappearedand a major product was exclusively formed. The reaction mixture wasdiluted with ethyl acetate (25 mL) and water (25 mL). The layers wereseparated and the aqueous layer was extracted with ethyl acetate (3×25mL). The combined organic layers were concentrated to afford anoff-white solid, which was suspended in methyl tert-butylether (MTBE, 20mL), stirred for 1 hour, and filtered. The solid was rinsed with methyltert-butylether (20 mL) and further dried under vacuum at roomtemperature (about 22° C.) for 4 hours to give a white solid (4.28 g,83%): mp 162-164° C.;

¹H NMR (400 MHz, DMSO-d₆) δ 12.90 (bs, 1H), 9.49 (s, 1H), 7.97 (s, 1H),2.02 (s, 3H); ¹³C NMR (101 MHz, DMSO-d₆) δ 167.81, 130.07, 123.72,116.73, 22.58; EIMS m/z 159 ([M]⁺).

Example 3: N-(3-Chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)acetamide (1c)

A 250 mL, 3-neck round bottom flask was charged withN-(3-chloro-1H-pyrazol-4-yl)acetamide (4.80 g, 30.1 mmol), copper(II)chloride (0.404 g, 3.01 mmol), 3-iodopyridine (7.40 g, 36.1 mmol),potassium phosphate (7.66 g, 36.1 mmol) and acetonitrile (100 mL).N,N′-Dimethylethane-1,2-diamine (1.326 g, 15.04 mmol) was added and themixture was heated at 80° C. for 18 hours, at which point thin layerchromatography analysis [Eluent: ethyl acetate] indicated that a traceof starting material remained and a major product formed. It wasfiltered through a pad of Celite® and the Celite® pad rinsed withacetonitrile (50 mL). Water (300 mL) was added to the filtrates and theresulting suspension was stirred for 2 hours and filtered. The resultingsolid was rinsed with water (2×20 mL) and dried under vacuum at roomtemperature to afford a white solid (4.6 g, 65%): mp 169-172° C.; ¹H NMR(400 MHz, DMSO-d₆) δ 9.84 (s, 1H), 9.05 (dd, J=2.8, 0.8 Hz, 1H), 8.82(s, 1H), 8.54 (dd, J=4.7, 1.4 Hz, 1H), 8.20 (ddd, J=8.4, 2.8, 1.4 Hz,1H), 7.54, (ddd, J=8.3, 4.7, 0.8 Hz, 1H), 2.11 (s, 3H); ¹³C NMR (101MHz, DMSO-d₆) δ 168.12, 147.46, 139.42, 135.46, 133.60, 125.47, 124.21,122.21, 120.16, 22.62; EIMS m/z 236 ([M]⁺).

Alternate Synthetic Route to Example 3:N-(3-Chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)acetamide

A 100-mL, 3-neck round bottom flask was charged with copper(I) chloride(59.6 mg, 0.602 mmol) and acetonitrile (10 mL),N,N′-dimethyethane-1,2-diamine (106 mg, 1.203 mmol) was added and themixture was stirred under nitrogen to afford a solution.N-(3-Chloro-1H-pyrazol-4-yl)acetamide (480 mg, 3.01 mmol) and potassiumcarbonate (K₂CO₃, 831 mg, 6.02 mmol) were added, followed by3-bromopyridine (570 mg, 3.61 mmol). The mixture was purged withnitrogen three times and heated at 80° C. for 18 hours. Thin layerchromatography analysis [Eluent: ethyl acetate], indicated that a traceof starting material remained and a major product formed. It wasfiltered through a pad of Celite® and the Celite® pad rinsed withacetonitrile (10 mL). The filtrates were concentrated to about 5 mL andwater (10 mL) was added to the resulting suspension. The resultingsuspension was stirred for 1 hour and filtered. The solid was rinsedwith water (2×5 mL) and dried under vacuum at room temperature to afforda white solid (458 mg, 64%). Characterization matched sample prepared byprevious method.

Alternate Synthetic route to Example 3:N-(3-Chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)acetamide

To a 4-neck round bottom flask was charged N,N′-dimethylformamide (DMF,250 mL) and was degassed 2-3 times. Copper(I) iodide (17.9 g, 94.0 mmol)was added, followed by N,N′-dimethylethane-1,2-diamine (16.2 g, 188mmol) at 25-30° C. The mixture was purged with nitrogen for 30 minutes.3-Bromopyridine (59.4 g, 376 mmol) was added, followed byN-(3-chloro-1H-pyrazol-4-yl)acetamide (50.0 g, 313 mmol) and potassiumcarbonate (87.0 g, 188 mmol) at 25-30° C. The reaction mixture waspurged with nitrogen for 30 minutes and heated at 95-100° C. for 3hours, at which point HPLC analysis indicated that the reaction wascomplete. It was cooled to 25-30° C. and water (1 L) was added over30-45 minutes. The resulting suspension was stirred at 25-30° C. for 30minutes and cooled to 0-10° C. It was stirred for 12 hours at 0-10° C.and filtered. The filter cake was rinsed with water (2×250 mL) and driedto afford an off-white solid (55 g, 74%). Characterization matchedsample prepared by previous method.

Example 4: 3-Chloro-N-ethyl-1-(pyridin-3-yl)-1H-pyrazol-amine (1d)

A 100 mL, 3-neck round bottom flask was charged withN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)acetamide (475 mg, 2.01mmol) and tetrahydrofuran (10 mL). borontrifluoride etherate (0.63 mL,5.02 mmol) was added and the mixture was stirred for 15 minutes to givea suspension. Sodium borohydride (228 mg, 6.02 mmol) was added and thereaction was heated at 60° C. for 4 hours, at which point thin layerchromatography analysis [Eluent: ethyl acetate, sample was prepared bytreatment of reaction mixture with hydrochloric acid, followed by sodiumbicarbonate basification and ethyl acetate extraction] indicated thatthe reaction was complete. Water (10 mL) and concentrated hydrochloricacid (1 mL) were added and the reaction was heated at 60° C. for 1 hour.The reaction mixture was cooled to room temperature and distilled toremove tetrahydrofuran. The reaction mixture was neutralized withsaturated sodium bicarbonate solution to pH 8 to afford a suspension,which was stirred for 1 hour and filtered. The filter cake was rinsedwith water (10 mL) and dried under vacuum to give a white solid (352 mg,79%): mp 93-96° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 8.99 (d, J=2.7 Hz, 1H),8.44 (dd, J=4.6, 1.4 Hz, 1H), 8.10 (ddd, J=8.4, 2.7, 1.4 Hz, 1H), 8.06(s, 1H), 7.50 (dd, J=0.4, 4.7 Hz, 1H), 4.63 (t, J=6.0 Hz, 1H), 3.06-2.92(m, 2H), 1.18 (t, J=7.1 Hz, 3H); ¹³C NMR (101 MHz, DMSO-d₆) δ 146.17,138.31, 135.81, 132.82, 130.84, 124.10, 123.96, 112.23, 40.51, 14.28;EIMS m/z 222 ([M]⁺).

Alternate Synthetic Route to Example 4:3-Chloro-N-ethyl-1-(pyridin-3-yl)-1H-pyrazol-amine Step 1.N-(3-Chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylacetamide (1c′)

To a 3-neck, 100-mL round bottom flask was chargedN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)acetamide (5.00 g, 21.1mmol) and tetrahydrofuran (50 mL). Sodium tert-butoxide (3.05 g, 31.7mmol) was added (causing a temperature rise from 22° C. to 27.9° C.),followed by ethyl bromide (4.70 mL, 63.4 mmol). The reaction was stirredat 35° C. for 168 hours, at which point HPLC analysis indicated thatonly 2.9% (area under the curve, AUC) starting material remained. Thereaction mixture was concentrated to give a brown residue, which wasdiluted with ethyl acetate (50 mL) and water (50 mL). The aqueous layerwas extracted with ethyl acetate (4×50 mL) and the combined organicswere concentrated to give a brown residue. The residue was dissolved indichloromethane (CH₂Cl₂, 2×10 mL) and purified by flash columnchromatography using 60-100% ethyl acetate/hexanes as eluent. Thefractions containing pure product were combined and concentrated toafford the title product as a yellow solid (4.20 g, 74%): mp: 87-91° C.;¹H NMR (400 MHz, CDCl₃) δ 8.98 (d, J=2.7, 0.8 Hz, 1H), 8.62 (dd, J=4.8,1.4 Hz, 1H), 8.06 (ddd, J=8.3, 2.7, 1.4 Hz, 1H), 8.00 (s, 1H), 7.47 (dd,J=8.3, 4.7 Hz, 1H), 3.71 (q, J=7.1 Hz, 2H), 1.97 (s, 3H), 1.16 (t, J=7.2Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 170.69, 148.56, 140.89, 139.95,135.64, 126.22, 126.08, 124.86, 124.09, 43.77, 22.27, 13.15; ESIMS m/z265 ([M+H]⁺).

Step 1. N-(3-Chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylacetamide(1c′)

To a 3-neck, 100-mL round bottom flask was chargedN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)acetamide (1.66 g, 7.0mmol) and tetrahydrofuran (16 mL). Sodium tert-butoxide (0.843 g, 8.77mmol, 1.25 eq) and ethyl bromide (0.78 mL, 10.52 mmol, 1.5 eq) wereadded and the reactor was capped with a septa. The reaction was stirredat 58° C. for 24 hours, at which point HPLC analysis indicated that only1.97% starting material remained. The mixture was concentrated to give abrown residue, which was dissolved in water (20 mL) and ethyl acetate(20 mL). The aqueous layer was extracted with ethyl acetate (2×20 mL)and the combined organics were concentrated to dryness. The residue waspassed through a silica gel plug (40 g silica) and eluted with ethylacetate (200 mL). The filtrates were concentrated to dryness and furtherdried under vacuum at 20° C. to afford a yellow solid (1.68 g, 89%).Characterization matched sample prepared by previous method.

Step 1. N-(3-Chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylacetamide(1c′)

In a 125 mL 3-neck round-bottomed flask was addedN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)acetamide (2.57 g, 9.44mmol), tetrahydrofuran (55 mL), and sodium tert-butoxide (1.81 g, 18.9mmol). The suspension was stirred for 5 minutes then ethyl bromide (1.41mL, 18.9 mmol), and tetrabutylammonium iodide (67 mg, 0.2 mmol) wereadded. The resulting gray colored suspension was then heated to 38° C.The reaction was analyzed after 3 hours and found to have gone to 81%completion, after 24 hours the reaction was found to have gone tocompletion. The reaction mixture was allowed to cool to ambienttemperature and quenched with ammonium hydroxide (NH₄OH)/formic acid(HCO₂H) buffer (10 mL). The mixture was then diluted withtetrahydrofuran (40 mL), ethyl acetate (120 mL), and saturated sodiumbicarbonate (30 mL). The layers were separated and the aqueous layer wasextracted with ethyl acetate (2×30 mL). The organic layers were combinedand silica gel (37 g) was added. The solvent was removed in vacuo togive a solid that was purified using semi-automated silica gelchromatography (RediSep Silica 220 g column; hexanes (0.2%triethylamine)/ethyl acetate, 40/60 to 0/100 gradient elution system,flow rate 150 mL/minutes) to give, after concentration, an orange solidweighing (2.19 g, 88%).

Step 2. 3-Chloro-N-ethyl-1-(pyridin-3-yl)-1H-pyrazol-amine (1d)

A solution ofN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylacetamide (1.8 g,6.80 mmol) in hydrochloric acid (1 N, 34 mL) was heated at 80° C. for 18hours, at which point HPLC analysis indicated that only 1.1% startingmaterial remained. The reaction mixture was cooled to 20° C. andbasified with sodium hydroxide (NaOH, 50 wt %) to pH>9. The resultingsuspension was stirred at 20° C. for 2 hours and filtered. The filtercake was rinsed with water (2×5 mL), conditioned for 30 minutes, andair-dried to afford an off-white solid (1.48 g, 95%): ¹H NMR (400 MHz,DMSO-d₆) δ 9.00 (dd, J=2.8, 0.8 Hz, 1H), 8.45 (dd, J=4.7, 1.4 Hz, 1H),8.11 (ddd, J=8.4, 2.8, 1.4 Hz, 1H), 8.06 (d, J=0.6 Hz, 1H), 7.49 (ddd,J=8.4, 4.7, 0.8 Hz, 1H), 4.63 (t, J=6.0 Hz, 1H), 3.00 (qd, J=7.1, 5.8Hz, 2H), 1.19 (t, J=7.1 Hz, 3H); ¹³C NMR (101 MHz, DMSO-d₆) δ 146.18,138.31, 135.78, 132.82, 130.84, 124.08, 123.97, 112.23, 40.51, 14.28;ESIMS m/z 223 ([M+H]⁺).

Alternate Synthetic Route to Example 4:3-Chloro-N-ethyl-1-(pyridin-3-yl)-1H-pyrazol-amine

To a 3-neck, 100-mL round bottom flask was chargedN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)acetamide (5 g, 21.13 mmol)and tetrahydrofuran (50 mL). Sodium tert-butoxide (4.06 g, 42.3 mmol)was added (causing a temperature rise from 22° C. to 27.6° C.), followedby ethyl bromide (6.26 mL, 85 mmol). The reaction was stirred at 35° C.for 144 hours at which point only 3.2% (AUC) starting material remained.The reaction mixture was concentrated to give a brown residue, which wasdissolved in hydrochloric acid (1 N, 106 mL, 106 mmol) and heated at 80°C. for 24 hours, at which point HPLC analysis indicated that thestarting material had been consumed. The reaction was cooled to 20° C.and basified with sodium hydroxide (50 wt %) to pH>9. The resultingsuspension was stirred at 20° C. for 1 hour and filtered, the filtercake was rinsed with water (25 mL) to afford a brown solid (5.18 g). Theresulting crude product was dissolved in ethyl acetate and passedthrough a silica gel plug (50 g) using ethyl acetate (500 mL) as eluent.The filtrate was concentrated to dryness to afford a white solid (3.8 g,80%).

Example 5:3-Chloro-N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylpropanamide(2a)

A 100 mL, three-neck round bottom flask was charged with3-chloro-N-ethyl-1-(pyridin-3-yl)-1H-pyrazol-amine (2.00 g, 8.98 mmol),ethyl acetate (20 mL), sodium bicarbonate (1.89 g, 22.5 mmol) was added,followed by dropwise addition of 3-chloropropanoyl chloride (1.37 g,10.78 mmol) at <20° C. The reaction was stirred at 10° C. for 2 hours,at which point thin layer chromatography analysis indicated that thereaction was complete [Eluent: ethyl acetate]. The reaction was dilutedwith water (50 mL) (off-gassing) and the layers separated. The aqueouslayer was extracted with ethyl acetate (20 mL) and the combined organiclayers were concentrated to dryness to afford a light brown oil whichwas purified by flash column chromatography using 80% ethylacetate/hexanes as eluent. The pure fractions were concentrated toafford a white solid (1.8 g, 64%): mp 87-90° C.; ¹H NMR (400 MHz,DMSO-d₆) δ 9.11 (dd, J=2.7, 0.7 Hz, 1H), 8.98 (s, 1H), 8.61 (dd, J=4.7,1.4, 1H), 8.25 (ddd, J=8.4, 2.7, 1.4 Hz, 1H), 7.61 (ddd, J=8.3, 4.7, 0.8Hz, 1H), 3.78 (t, J=6.3 Hz, 2H), 3.63 (q, J=7.1 Hz, 2H), 2.62 (t, J=6.2Hz, 2H), 1.10 (t, J=7.1 Hz, 3H); ¹³C NMR (101 MHz, DMSO-d₆) δ 169.13,148.13, 139.71, 139.12, 135.27, 129.42, 125.84, 124.24, 122.38, 43.12,40.10, 36.28, 12.78; EIMS m/z 312 ([M]⁺).

Example 6:N-(3-Chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-((3,3,3-trifluoropropyl)thio)propanamide(Compound 6.2)

A 100 mL, 3-neck round bottom flask was charged with3-chloro-N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylpropanamide(500 mg, 1.60 mmol) and methanol (10 mL), potassium hydroxide (107 mg,1.92 mmol) was added, followed by 3,3,3-trifluoro-propane-1-thiol (249mg, 1.92 mmol) The mixture was heated at 50° C. for 4 hours, at whichpoint thin layer chromatography analysis [Eluent: ethyl acetate]indicated the reaction was complete to give exclusively a new product.The reaction mixture was cooled to 20° C. and diluted with water (20 mL)and ethyl acetate (20 mL). The layers were separated and the aqueouslayer was extracted with ethyl acetate (20 mL). The organics were driedover sodium sulfate (Na₂SO₄) and concentrated to dryness to afford alight yellow oil, which solidified upon standing to give a light yellowsolid (650 mg, quantitative).

Example 7:N-(3-Chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-((3,3,3-trifluoropropyl)sulfoxo)propanamide(Compound 7.2)

N-(3-Chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-((3,3,3-trifluoropropyl)thio)propanamide(57.4 g, 141 mmol) was stirred in methanol (180 mL). To the resultingsolution was added hydrogen peroxide (43.2 mL, 423 mmol) dropwise usinga syringe. The solution was stirred at room temperature for 6 hours, atwhich point LCMS analysis indicated that the starting material wasconsumed. The mixture was poured into dichloromethane (360 mL) andwashed with aqueous sodium carbonate (Na₂CO₃). The organic layer wasdried over sodium sulfate and concentrated to provide a thick yellowoil. The crude product was purified by flash column chromatography using0-10% methanol/ethyl acetate as eluent and the pure fractions werecombined and concentrated to afford the desired product as an oil (42.6g, 68%): ¹H NMR (400 MHz, DMSO-d₆) δ 9.09 (dd, J=2.8, 0.7 Hz, 1H), 8.98(s, 1H), 8.60 (dd, J=4.7, 1.4 Hz, 1H), 8.24 (ddd, J=8.4, 2.7, 1.4 Hz,1H), 7.60 (ddd, J=8.4, 4.7, 0.8 Hz, 1H), 3.61 (q, J=7.4, 7.0 Hz, 2H),3.20-2.97 (m, 2H), 2.95-2.78 (m, 2H), 2.76-2.57 (m, 2H), 2.58-2.45 (m,2H), 1.09 (t, J=7.1 Hz, 3H); ESIMS m/z 423 ([M+H]⁺).

Example PE-1: Prophetic Preparation of(2,2-difluorocyclopropyl)methanethiol

To a solution of 2-(bromomethyl)-1,1-difluorocyclopropane (about 1 eq)in a solvent, such as methanol (at a concentration ranging from about0.01 M to about 1 M), at temperatures between about 0° C. and about 40°C. may be added thioacetic acid (about 1 eq to about 2 eq), and a base,such as potassium carbonate (about 1 eq to 2 eq). An additional amountof a base, such as potassium carbonate (about 1 eq to 2 eq) may be addedafter a time ranging from about 30 minutes to 2 hours to the mixture toremove the acyl group. The reaction may be stirred until it isdetermined to be complete. The product may then be obtained usingstandard organic chemistry techniques for workup and purification.

Alternative preparation of (2,2-difluorocyclopropyl)methanethiol: To asolution of 2-(bromomethyl)-1,1-difluorocyclopropane (about 1 eq) in asolvent, such as methanol (at a concentration ranging from about 0.01 Mto about 1 M), at temperatures between about 0° C. and about 40° C. maybe added thioacetic acid (about 1 eq to about 2 eq), and a base, such aspotassium carbonate (about 1 eq to 2 eq). The intermediate thioesterproduct may then be obtained using standard organic chemistry techniquesfor workup and purification. To the thioester (about 1 eq) in a solvent,such as methanol (at a concentration ranging from about 0.01 M to about1 M), at temperatures between about 0° C. and about 40° C. may be addeda base, such as potassium carbonate (about 1 eq to 2 eq). The reactionmay be stirred until it is determined to be complete. The product maythen be obtained using standard organic chemistry techniques for workupand purification.

BIOLOGICAL EXAMPLES Example A Bioassays on Green Peach Aphid (“GPA”)(Myzus persicae) (MYZUPE

GPA is the most significant aphid pest of peach trees, causing decreasedgrowth, shriveling of leaves, and the death of various tissues. It isalso hazardous because it acts as a vector for the transport of plantviruses, such as potato virus Y and potato leafroll virus to members ofthe nightshade/potato family Solanaceae, and various mosaic viruses tomany other food crops. GPA attacks such plants as broccoli, burdock,cabbage, carrot, cauliflower, daikon, eggplant, green beans, lettuce,macadamia, papaya, peppers, sweet potatoes, tomatoes, watercress andzucchini among other plants. GPA also attacks many ornamental crops suchas carnations, chrysanthemum, flowering white cabbage, poinsettia androses. GPA has developed resistance to many pesticides.

Several molecules disclosed herein were tested against GPA usingprocedures described below.

Cabbage seedling grown in 3-in pots, with 2-3 small (3-5 cm) trueleaves, were used as test substrate. The seedlings were infested with20-5-GPA (wingless adult and nymph stages) one day prior to chemicalapplication. Four pots with individual seedlings were used for eachtreatment. Test compounds (2 mg) were dissolved in 2 mL ofacetone/methanol (1:1) solvent, forming stock solutions of 1000 ppm testcompound. The stock solutions were diluted 5× with 0.025% Tween 20 inwater to obtain the solution at 200 ppm test compound. A hand-heldaspirator-type sprayer was used for spraying a solution to both sides ofthe cabbage leaves until runoff. Reference plants (solvent check) weresprayed with the diluent only containing 20% by volume acetone/methanol(1:1) solvent. Treated plants were held in a holding room for three daysat approximately 25° C. and ambient relative humidity (RH) prior tograding. Evaluation was conducted by counting the number of live aphidsper plant under a microscope. Percent Control was measured by usingAbbott's correction formula (W. S. Abbott, “A Method of Computing theEffectiveness of an Insecticide” J. Econ. Entomol 18 (1925), pp.265-267) as follows.Corrected % Control=100*(X−Y)/X

where

X=No. of live aphids on solvent check plants and

Y=No. of live aphids on treated plants

The results are indicated in the table entitled “Table 1: GPA (MYZUPE)and sweetpotato whitefly-crawler (BEMITA) Rating Table”.

Example B Bioassays on Sweetpotato Whitefly Crawler (Bemisia tabaci)(BEMITA.)

The sweetpotato whitefly, Bemisia tabaci (Gennadius), has been recordedin the United States since the late 1800s. In 1986 in Florida, Bemisiatabaci became an extreme economic pest. Whiteflies usually feed on thelower surface of their host plant leaves. From the egg hatches a minutecrawler stage that moves about the leaf until it inserts itsmicroscopic, threadlike mouthparts to feed by sucking sap from thephloem. Adults and nymphs excrete honeydew (largely plant sugars fromfeeding on phloem), a sticky, viscous liquid in which dark sooty moldsgrow. Heavy infestations of adults and their progeny can cause seedlingdeath, or reduction in vigor and yield of older plants, due simply tosap removal. The honeydew can stick cotton lint together, making it moredifficult to gin and therefore reducing its value. Sooty mold grows onhoneydew-covered substrates, obscuring the leaf and reducingphotosynthesis, and reducing fruit quality grade. It transmittedplant-pathogenic viruses that had never affected cultivated crops andinduced plant physiological disorders, such as tomato irregular ripeningand squash silverleaf disorder. Whiteflies are resistant to manyformerly effective insecticides.

Cotton plants grown in 3-inch pots, with 1 small (3-5 cm) true leaf,were used at test substrate. The plants were placed in a room withwhitely adults. Adults were allowed to deposit eggs for 2-3 days. Aftera 2-3 day egg-laying period, plants were taken from the adult whiteflyroom. Adults were blown off leaves using a hand-held Devilbliss sprayer(23 psi). Plants with egg infestation (100-300 eggs per plant) wereplaced in a holding room for 5-6 days at 82° F. and 50% RH for egg hatchand crawler stage to develop. Four cotton plants were used for eachtreatment. Compounds (2 mg) were dissolved in 1 mL of acetone solvent,forming stock solutions of 2000 ppm. The stock solutions were diluted10× with 0.025% Tween 20 in water to obtain a test solution at 200 ppm.A hand-held Devilbliss sprayer was used for spraying a solution to bothsides of cotton leaf until runoff. Reference plants (solvent check) weresprayed with the diluent only. Treated plants were held in a holdingroom for 8-9 days at approximately 82° F. and 50% RH prior to grading.Evaluation was conducted by counting the number of live nymphs per plantunder a microscope. Insecticidal activity was measured by using Abbott'scorrection formula (see above) and presented in Table 1.

TABLE 1 GPA (MYZUPE) and sweetpotato whitefly-crawler (BEMITA) RatingTable Example Compound BEMITA MYZUPE 1a B B 1b B B 1c B B 1d B B 2a A ACompound 6.2 A A Compound 7.2 A A

% Control of Mortality Rating 80-100 A More than 0-Less than 80 B NotTested C No activity noticed in this bioassay D

COMPARATIVE EXAMPLES Example CE-1: N-(1-Acetyl-1H-pyrazol-4-yl)acetamide

A 250-mL 3-neck flask was charged with 1H-pyrazol-4-amine (5 g, 60.2mmol) and dichloromethane (50 mL). The resulting suspension was cooledto 5° C. and triethylamine (9.13 g, 90.0 mmol) was added, followed byacetic anhydride (7.37 g, 72.2 mmol) at <20° C. The reaction was stirredat room temperature for 18 hours, at which point thin layerchromatography [Eluent: ethyl acetate] analysis indicated that thereaction was incomplete. Additional triethylamine (4.57 g, 45.0 mmol)and acetic anhydride (3.70 g, 36.0 mmol) were added and the reaction washeated at 30° C. for an additional 3 hours to give a dark solution, atwhich point thin layer chromatography analysis indicated that only atrace of starting material remained. The reaction mixture was purifiedby flash column chromatography using ethyl acetate as eluent. Thefractions containing pure product were combined and concentrated todryness to afford an off-white solid. The solid was dried under vacuumat room temperature for 18 hours (5.55 g, 55%):

¹H NMR (400 MHz, DMSO-d₆) δ 10.30 (s, 1H), 8.39 (d, J=0.7 Hz, 1H), 7.83(d, J=0.7 Hz, 1H), 2.60 (s, 3H), 2.03 (s, 3H); EIMS m/z 167 ([M]⁺).

Example CE-2: N-(3-Bromo-1H-pyrazol-4-yl)acetamide

A 250 mL 3-neck round bottom flask was charged with1H-pyraz-4-amine-hydrobromide (4.00 g, 24.7 mmol) and water (23 mL). Tothe mixture, sodium bicarbonate (8.30 g, 99.0 mmol) was added slowlyover 10 minutes, followed by tetrahydrofuran (23 mL). The mixture wascooled to 5° C. and acetic anhydride (2.60 g, 25.4 mmol) was added over30 minutes while maintaining the internal temperature at <10° C. Thereaction mixture was stirred at ˜5° C. for 20 minutes, at which point ¹HNMR and UPLC analyses indicated that the starting material was consumedand the desired product as well as bis-acetylated byproduct were formed.The reaction was extracted with ethyl acetate and the organic layerswere dried over magnesium sulfate (MgSO₄) and concentrated. The crudemixture was triturated with methyl tert-butylether to remove thebisacetylated product to afford ˜1.24 g of a white solid. ¹H NMRanalysis showed it was 1:1.1 desired to undesired bisacetylated product.The solid was purified by flash column chromatography using 50-100%ethyl acetate/hexanes as eluent to afford the desired product as a whitesolid (380 mg, 7.5%) and the bisacetylated product as a white solid(˜800 mg): ¹H NMR (400 MHz, DMSO-d₆) δ 13.01 (s, 1H), 9.36 (s, 1H), 7.92(s, 1H), 2.03 (s, 3H); ¹³C NMR (101 MHz, DMSO-d₆) δ 167.94, 123.93,119.19, 119.11, 22.63; ESIMS m/z 204 ([M+H]⁺).

It should be understood that while this invention has been describedherein in terms of specific embodiments set forth in detail, suchembodiments are presented by way of illustration of the generalprinciples of the invention, and the invention is not necessarilylimited thereto. Certain modifications and variations in any givenmaterial, process step or chemical formula will be readily apparent tothose skilled in the art without departing from the true spirit andscope of the present invention, and all such modifications andvariations should be considered within the scope of the claims thatfollow.

What is claimed is:
 1. A process comprising: (a) halogenating andreducing 4-nitropyrazole to produce

3-chloro-1H-pyrazol-4-amine hydrochloride (1a)

with concentrated hydrochloric acid at a temperature between about 10°C. and about 20° C. with between about 1 and about 4 equivalents oftriethylsilane and about 1 to 10 weight percent palladium on alumina;(b) mono-acylating 3-chloro-1H-pyrazol-4-amine hydrochloride (1a) withacetic anhydride in the presence of a base to yield

(c) reacting 1(b) with a suitable halopyridine in the presence of acopper salt, an amine, and a base, to yieldN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)acetamide (1c)

(d) reacting 1(c) with a suitable reducing agent in the presence of anacid to yield 3-chloro-N-ethyl-1-(pyridin-3-yl)-1H-pyrazol-amine (1d)

(e) reacting (1d) with between about 1 and about 2 equivalents of3-chloropropionyl chloride in the presence of a inorganic base to yieldN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylpropanamide (2a)

and (f) reacting (2a) with a thiol HS-R¹ in the presence of a base toyield pesticidal thioethers (2b)

wherein R¹ is selected form the group consisting of C₁-C₄ haloalkyl andC₁-C₄ alkyl-C₃-C₆ halocycloalkyl.
 2. A process according to claim 1,wherein R¹ is C₁-C₄ haloalkyl.
 3. A process according to claim 1,wherein R¹ is CH₂CH₂CF₃.
 4. A process according to claim 1, wherein R¹is CH₂(2,2-difluorocyclopropyl).
 5. A process according to claim 1further comprising oxidizing (2b) with an oxidizing agent comprisinghydrogen peroxide to yield


6. The process of claim 1, wherein the base in step (b) or step (e) issodium bicarbonate.
 7. The process of claim 1, wherein step (b) iscarried out at a temperature of from about 0° C. to about 10° C.
 8. Theprocess of claim 1, wherein the halopyridine in step (c) is3-bromopyridine or 3-iodopyridine.
 9. The process of claim 1, whereinthe copper salt in step (c) is copper(I) chloride (CuCl), copper(II)chloride (CuCl₂), or copper(I) iodide (CuI).
 10. The process of claim 1,wherein the copper salt in step (c) is copper(I) iodide (CuI).
 11. Theprocess of claim 1, wherein the base in step (c) is potassium phosphate(K₃PO₄).
 12. The process of claim 1, wherein the amine in step (c) isN,N′-dimethylethane-1,2-diamine.
 13. The process of claim 1, whereinstep (c) is carried out at a temperature of from about 50° C. to about110° C.
 14. The process of claim 1, wherein step (c) is carried out inthe presence of a polar solvent.
 15. The process of claim 2, wherein thepolar solvent in step (c) is acetonitrile (MeCN), dioxane, orN,N-dimethylformamide.
 16. The process of claim 1, wherein the reducingagent in step (d) is a hydride source.
 17. The process of claim 16,wherein the hydride source in step (d) is sodium borohydride (NaBH₄).18. The process of claim 1, wherein the acid in step (d) is a Lewisacid.
 19. The process of claim 18, wherein the Lewis acid in step (d) isborontrifluoride etherate (BF₃.Et₂O).
 20. The process of claim 1,wherein the base in step (f) is potassium hydroxide (KOH).